Study reveals new player in sepsis-associated acute respiratory distress syndrome
Every year, more than 200, 000 Americans die from sepsis, a severe illness caused by bacterial infection of the bloodstream. A study by Vikas Sukhatme and colleagues (Beth Israel Deaconess Medical Center and Harvard Medical School) now reveals that a protein called angiopoietin-2 may play a pivotal role in acute respiratory distress syndrome (ARDS), a condition that affects about 40% of patients with sepsis and worsens their prognosis.
In ARDS, small blood vessels in the lungs become leaky and release fluid. This impairs lung function, and patients experience trouble breathing and need to be put on respirators. If the condition lasts too long, the lung tissue gets damaged irreversibly. But what causes the leakage of fluid out of the blood vessels?
Blood vessels are normally lined with tightly linked cells, called endothelial cells, that form an impermeable barrier. Animal experiments had suggested that the development of this barrier is controlled by two small proteins called angiopoietin-1 (Ang-1) and angoipoietin-2 (Ang-2) together with these proteins' receptor, called Tie 2. These experiments also suggested that Ang-2 might disrupt the barrier lining the blood vessel wall. These and other observations prompted Sukhatme's team to ask whether the Tie-2 signaling pathway is affected in sepsis and, specifically, whether excess Ang-2 levels might promote the leakage of fluid from the blood vessels that underlies ARDS.
They tested whether excess levels of Ang-2 occur in sepsis and could cause leakiness of lung blood vessels in three different ways: First, they measured the level of Ang-2 in the blood of patients with sepsis. Second, they tested whether blood from patients with sepsis could cause leakiness in blood vessels grown in the laboratory. Finally, they tested whether elevated levels of Ang-2 affect the permeability of lung blood vessels in mice. They found that Ang-2 levels are elevated in patients with sepsis, especially in those who have acute lung injury. Over the course of the disease, Ang-2 levels mirror a patient's condition: they go up as the condition worsens and go down as the patient gets better. They then showed that treating blood vessels grown in the laboratory with blood from patients with ARDS made these blood vessels leaky. They could get the same results with treating the blood vessels with just Ang-2, and they could reverse the leakiness by subsequent treatment with Ang-1, a molecule that antagonizes the actions of Ang-2. Finally, consistent with a key role for Ang-2 in sepsis-associated ARDS, they found that injecting Ang-2 into the blood of healthy mice caused ARDS-like symptoms in these animals.
These results suggest that Ang-2 can serve as a marker of acute lung injury and might be a key player in sepsis-associated ARDS. They raise the possibility that reducing Ang-2 levels in patients might help to prevent or improve this dangerous complication in patients with sepsis. Future studies in patients with sepsis, and in patients with ARDS that is not caused by sepsis, are needed to clarify the roles of Ang-2 and Tie-2 in ARDS and the suitability of Ang-2 as a target for therapy.
Citation: Parikh S, Mammoto T, Schultz A, Yuan HT, Christiani D, et al. (2006) Excess circulating angiopoietin-2 may contribute to pulmonary vascular leak in sepsis in humans. PLoS Med 3(3): e46.
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